JP7498147B2 - Method for Purifying Apixaban - Google Patents
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- JP7498147B2 JP7498147B2 JP2021079975A JP2021079975A JP7498147B2 JP 7498147 B2 JP7498147 B2 JP 7498147B2 JP 2021079975 A JP2021079975 A JP 2021079975A JP 2021079975 A JP2021079975 A JP 2021079975A JP 7498147 B2 JP7498147 B2 JP 7498147B2
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- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims description 69
- 229960003886 apixaban Drugs 0.000 title claims description 66
- 238000000034 method Methods 0.000 title claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000012046 mixed solvent Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 235000011181 potassium carbonates Nutrition 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 description 27
- 238000000746 purification Methods 0.000 description 24
- 239000002904 solvent Substances 0.000 description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 8
- 125000004494 ethyl ester group Chemical group 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940047562 eliquis Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
本発明は、アピキサバンの新規な精製方法に関する。 The present invention relates to a novel method for purifying apixaban.
下記化学式： Chemical formula below:
で示される化学名：１－（４－メトキシフェニル）－７－オキソ－６－［４－（２－オキソピペリジン－１－イル）フェニル］－４，５，６，７－テトラヒドロ－１Ｈ－ピラゾロ［３，４－ｃ］ピリジン－３－カルボキサミドを有するアピキサバン（ＩＮＮ）は、経***性化血液凝固第Ｘ因子（ＦＸａ）阻害剤として、臨床的にエリキュース（登録商標）錠の名称で、静脈血栓塞栓症（深部静脈血栓症及び肺血栓塞栓症）の治療及び再発抑制に使用されている薬物である（非特許文献１）。 Apixaban (INN), which has the chemical name 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, is an orally active blood coagulation factor X (FXa) inhibitor that is clinically used under the name Eliquis (registered trademark) tablets to treat and prevent recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism) (Non-Patent Document 1).
アピキサバン原薬中には、その製造方法に起因して、下式で示すメチルエステル体、エチルエステル体、カルボン酸体： Due to the manufacturing process, apixaban drug substance contains the methyl ester, ethyl ester, and carboxylic acid forms shown in the following formulas:
が不純物として含有されている。
そのため、アピキサバンの精製方法が提案されており、例えば、炭素数が１から４の低級アルコール、アセトン、ＤＭＦまたはＤＭＳＯ中で、塩基として、トリエチルアミン、アンモニア水、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウムまたは炭酸水素カリウムを加えて再結晶することにより、これら不純物が低減されることを報告されている（特許文献１）。
is contained as an impurity.
Therefore, a method for purifying apixaban has been proposed. For example, it has been reported that these impurities can be reduced by recrystallization in a lower alcohol having 1 to 4 carbon atoms, acetone, DMF, or DMSO with the addition of triethylamine, aqueous ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate as a base (Patent Document 1).
具体的には、下記表１に上記特許文献に記載されている再結晶の結果を示した（なお、再結晶前のアピキサバンの品質（純度）に関する情報は、当該文献から読み取れない）。 Specifically, the results of the recrystallization described in the above patent document are shown in Table 1 below (note that no information regarding the quality (purity) of apixaban before recrystallization can be obtained from the patent document).
しかしながら、アピキサバンは難溶性の原薬であるため、上記方法では大量の再結晶溶媒を必要とし、また再結晶収率も低く、メチルエステル体、エチルエステル体、カルボン酸体等の類縁物質の除去性も十分ではないため、工業的な精製方法としては好ましいものではない。
したがって、類縁物質の除去性が高く、工業的に応用できるアピキサバンの精製方法が求められているのが現状である。
However, since apixaban is a poorly soluble drug substance, the above method requires a large amount of recrystallization solvent, has a low recrystallization yield, and is not sufficient to remove related substances such as methyl esters, ethyl esters, and carboxylic acids, making it unsuitable as an industrial purification method.
Therefore, there is currently a demand for a purification method for apixaban that is highly capable of removing related substances and can be applied industrially.
本発明は、これら先行技術に鑑み、アピキサバンについて、類縁物質の除去性が高く、再結晶収率がよく、工業的に応用し得る精製方法を提供することを課題とする。
かかる課題を解決するべく、本発明者らは、アピキサバンの再結晶による精製方法について種々検討した結果、アピキサバンの再結晶溶媒としてアセトニトリル及び水の混合溶媒を使用し、塩基を加えて再結晶することで、類縁物質を効率的に除去し、収率よくアピキサバンを精製し得ることを見出し、本発明を完成させるに至った。
In view of the above prior art, an objective of the present invention is to provide a purification method for apixaban which is highly capable of removing related substances, has a good recrystallization yield, and can be industrially applied.
In order to solve these problems, the present inventors have investigated various methods for purifying apixaban by recrystallization, and as a result, have found that by using a mixed solvent of acetonitrile and water as a recrystallization solvent for apixaban and recrystallizing by adding a base, related substances can be efficiently removed and apixaban can be purified in high yield, thereby completing the present invention.
したがって、本発明は、以下の態様に基づくものである。
（１）アピキサバンをアセトニトリル及び水の混合溶媒中、塩基を加えて再結晶することを特徴とするアピキサバンの精製方法、
（２）塩基として、炭酸カリウム、炭酸水素カリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化ナトリウム、ナトリウムメトキシド、アンモニア水またはトリエチルアミンより選択される塩基を使用する上記（１）に記載のアピキサバンの精製方法、
（３）塩基の添加当量が、アピキサバンに対して０．０１～０．５当量である上記（１）または（２）に記載のアピキサバンの精製方法。
Therefore, the present invention is based on the following aspects.
(1) A method for purifying apixaban, comprising recrystallizing apixaban in a mixed solvent of acetonitrile and water by adding a base;
(2) The method for purifying apixaban according to the above (1), wherein the base used is selected from potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, aqueous ammonia, or triethylamine.
(3) The method for purifying apixaban according to (1) or (2) above, wherein the equivalent of the base added is 0.01 to 0.5 equivalents relative to apixaban.
本発明により、多量の再結晶溶媒を使用することなく、高品質かつ高収率でアピキサバンを得ることが可能となり、生産性が高く、工業的に応用し得るアピキサバンの精製方法が提供される。
本発明の精製方法で得られたアピキサバンは、更に含水エタノールなどで再結晶することにより、医薬品として用いるのに申し分のない、高品質のアピキサバンを得ることができるものであり、その効果は多大なものである。
According to the present invention, it is possible to obtain apixaban with high quality and in high yield without using a large amount of a recrystallization solvent, and a highly productive and industrially applicable purification method for apixaban is provided.
The apixaban obtained by the purification method of the present invention can be further recrystallized with aqueous ethanol or the like to obtain high-quality apixaban that is satisfactory for use as a pharmaceutical, and the effects thereof are significant.
以下に、本発明者らが検討した試験例の詳細を記すことにより、本発明をさらに詳細に説明していく。 The present invention will be explained in more detail below by providing details of the test examples examined by the inventors.
なお、本発明の検討に使用した製造後のアピキサバン粗製物の純度を、下記表２に示した。エチルエステル体は未検出であった。 The purity of the crude apixaban after production used in the study of the present invention is shown in Table 2 below. No ethyl ester was detected.
ところで、アピキサバン粗製物中に残存する不純物の一つであるカルボン酸体は、塩基を使用しない再結晶では精製効果が低い。また、アピキサバンは難溶性の原薬であり、何れの溶媒に対しても溶解度が低いため、再結晶での精製では、使用溶媒量が多くなる。
その点を確認するため、最初に、特許文献１に記載される再結晶を検討した。
その結果、再結晶溶媒として大量の溶媒を使用せざるを得ず、また、得られるアピキサバンの再結晶収率も極めて低い上、類縁物質の除去性も低いものであった。
特許文献１には、再結晶溶媒として、炭素数が１から４の低級アルコール、アセトン、ＤＭＦおよびＤＭＳＯのみが開示されている。そこで、再結晶溶媒を変更することによるアピキサバンの精製を検討した。
However, the carboxylic acid form, which is one of the impurities remaining in the crude apixaban, is poorly purified by recrystallization without using a base. In addition, since apixaban is a poorly soluble drug substance and has low solubility in any solvent, a large amount of solvent is used for purification by recrystallization.
In order to confirm this point, the recrystallization described in Patent Document 1 was first examined.
As a result, a large amount of solvent had to be used as the recrystallization solvent, the recrystallization yield of apixaban obtained was extremely low, and the removability of related substances was also low.
Patent Document 1 discloses only lower alcohols having 1 to 4 carbon atoms, acetone, DMF, and DMSO as recrystallization solvents. Therefore, the purification of apixaban by changing the recrystallization solvent was investigated.
以下に、実施例に代えて、本発明者らが検討した試験例の詳細を記載する。 In place of examples, the following provides details of test examples investigated by the inventors.
試験例１：再結晶溶媒の検討
アピキサバン粗製物（３ｇ）を下記表３に示す溶媒および炭酸カリウム（０．０５当量）を加えて加熱攪拌した。溶解を確認した後、活性炭（０．０６ｇ）を加えて１０分間加熱攪拌し、セライトろ過により活性炭を除いた。得られたろ液を再度加熱し、高温度で水（３０ｍＬ）を加えた。水を加え終わった後に、２５℃まで冷却し、ろ過した。ろ過物を水（６ｍＬ）とエタノール（６ｍＬ）で洗浄した後、４０℃で減圧乾燥し、アピキサバンを白色結晶として得た。その結果を、塩基を添加しない例も含め、下記表３中にまとめて示した。
Test Example 1: Study of recrystallization solvent Apixaban crude product (3 g) was heated and stirred with the solvent and potassium carbonate (0.05 equivalents) shown in Table 3 below. After confirming dissolution, activated carbon (0.06 g) was added and heated and stirred for 10 minutes, and the activated carbon was removed by celite filtration. The obtained filtrate was heated again and water (30 mL) was added at high temperature. After the addition of water was completed, it was cooled to 25°C and filtered. The filtrate was washed with water (6 mL) and ethanol (6 mL) and then dried under reduced pressure at 40°C to obtain apixaban as white crystals. The results, including the case where no base was added, are summarized in Table 3 below.
表中の結果から、その収率、純度および使用溶媒量の観点からみて、アセトニトリル／水の混合溶媒が好ましいことが判明した。
すなわち、精製効果が高い溶媒としては、アセトニトリル／水の混合溶媒、或いはアセトン／水の混合溶媒が挙げられるが、収率の面でアセトニトリル／水の混合溶媒が優れている。そのほかの溶媒では、カルボン酸体の除去効果が劣るものであった。
なお、トルエンと酢酸エチルについては、アピキサバンが溶解しないため、スラリー洗浄による結果を示した。
また、塩基を加えない場合、メチルエステル体およびカルボン酸体の除去率が低下することが判明した。
よって、精製効果と収率、生産性の面で最も優れている精製条件は、アセトニトリル／水の混合溶媒中で塩基を使用した条件であった。
アセトニトリル／水の混合溶媒については、先行特許文献１には開示も示唆もされていない。そこで、当該混合溶媒を使用し、塩基の検討を行った。
From the results in the table, it was found that the mixed solvent of acetonitrile/water was preferable in terms of the yield, purity and amount of solvent used.
That is, examples of solvents with high purification efficiency include a mixed solvent of acetonitrile/water and a mixed solvent of acetone/water, but the mixed solvent of acetonitrile/water is superior in terms of yield. Other solvents have poor removal efficiency of carboxylic acid bodies.
As apixaban does not dissolve in toluene and ethyl acetate, the results shown are those of slurry washing.
It was also found that the removal rates of methyl esters and carboxylic acids decreased when a base was not added.
Therefore, the most excellent purification conditions in terms of purification effect, yield, and productivity were those in which a base was used in an acetonitrile/water mixed solvent.
A mixed solvent of acetonitrile/water is neither disclosed nor suggested in Prior Patent Document 1. Therefore, the mixed solvent was used to study the base.
試験例２：各種塩基の添加効果（再結晶溶媒としてアセトニトリル／水混合溶媒を使用）
アピキサバン粗製物（３ｇ）をアセトニトリル（１５ｍＬ）と水（６ｍＬ）、下記表４に示す塩基（０．０５当量）を加えて加熱攪拌した。溶解を確認した後、活性炭（０．０６ｇ）を加えて１０分間加熱攪拌し、セライトろ過により活性炭を除いた。得られたろ液を再度加熱し、高温度で水（３０ｍＬ）を加えた。水を加え終わった後に、２５℃まで冷却し、ろ過した。ろ過物を水（６ｍＬ）とエタノール（６ｍＬ）で洗浄した後、４０℃で減圧乾燥し、アピキサバンを白色結晶として得た。
その結果を下記表４中に併せて示した。
Test Example 2: Effect of Adding Various Bases (Using an Acetonitrile/Water Mixture as the Recrystallization Solvent)
Apixaban crude product (3 g) was added to acetonitrile (15 mL), water (6 mL), and a base (0.05 equivalents) shown in Table 4 below, and the mixture was heated and stirred. After confirming dissolution, activated carbon (0.06 g) was added, heated and stirred for 10 minutes, and the activated carbon was removed by celite filtration. The obtained filtrate was heated again, and water (30 mL) was added at a high temperature. After the addition of water was completed, the mixture was cooled to 25°C and filtered. The filtrate was washed with water (6 mL) and ethanol (6 mL), and then dried under reduced pressure at 40°C to obtain apixaban as white crystals.
The results are shown in Table 4 below.
表中に示した結果から判明するように、アセトニトリル／水の混合溶媒中であれば、いずれの塩基を添加するかに関わらず、アピキサバンが良好に精製されていることが理解される。
したがって、添加する塩基としては、炭酸カリウム、炭酸水素カリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化ナトリウム、ナトリウムメトキシド、アンモニア水またはトリエチルアミンより選択することができ、これらに限定されるものではないが、炭酸カリウムがより好ましいものである。
そこで、使用する塩基として、炭酸カリウムを選択し、その添加量について検討を加えた。
As can be seen from the results shown in the table, apixaban was well purified in the acetonitrile/water mixed solvent, regardless of the addition of any base.
Therefore, the base to be added can be selected from potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, aqueous ammonia, or triethylamine, and is not limited thereto, but potassium carbonate is more preferred.
Therefore, potassium carbonate was selected as the base to be used, and the amount of addition was investigated.
試験例３：塩基の添加量の検討
アピキサバン粗製物（３ｇ）をアセトニトリル（１５ｍＬ）と水（６ｍＬ）、炭酸カリウム（０．０１～０．５当量）を加えて加熱攪拌した。溶解を確認した後、活性炭（０．０６ｇ）を加えて１０分間加熱攪拌し、セライトろ過により活性炭を除いた。得られたろ液を再度加熱し、高温度で水（３０ｍＬ）を加えた。水を加え終わった後に、２５℃まで冷却し、ろ過した。ろ過物を水（６ｍＬ）とエタノール（６ｍＬ）で洗浄した後、４０℃で減圧乾燥し、アピキサバンを白色結晶として得た。
その結果を、下記表５に示した。
Test Example 3: Study of the amount of base added Apixaban crude product (3 g) was added to acetonitrile (15 mL), water (6 mL), and potassium carbonate (0.01 to 0.5 equivalents) and heated and stirred. After confirming dissolution, activated carbon (0.06 g) was added and heated and stirred for 10 minutes, and the activated carbon was removed by celite filtration. The obtained filtrate was heated again, and water (30 mL) was added at a high temperature. After the addition of water was completed, it was cooled to 25°C and filtered. The filtrate was washed with water (6 mL) and ethanol (6 mL) and then dried under reduced pressure at 40°C to obtain apixaban as white crystals.
The results are shown in Table 5 below.
以上の検討結果から、使用する塩基の量としては、０．０１当量から０．５当量までの範囲であっても、いずれも良好な結果を与えたが、塩基の使用量の低減からみれば、その使用量として、０．０１当量から０．１当量程度であるのが良い。 From the above results, good results were obtained using amounts of base ranging from 0.01 to 0.5 equivalents, but from the viewpoint of reducing the amount of base used, it is best to use an amount of about 0.01 to 0.1 equivalents.
ところで、通常、アピキサバン粗製物中には不純物として、上記したメチルエステル体、エチルエステル体、カルボン酸体の３種類が含まれていることが知られている。
上記した精製方法の検討にあっては、アピキサバン粗製物ではエチルエステル体は未検出であった。そこで、前記した表２の純度を有する粗製物にエチルエステル体を添加し、以下の表６に示す純度の、メチルエステル体、エチルエステル体、カルボン酸体の３種類が不純物として含有されるアピキサバン粗製物を調製し、以下の検討に使用した。
Incidentally, it is known that crude apixaban usually contains the above-mentioned three types of impurities, that is, the methyl ester, the ethyl ester, and the carboxylic acid.
In the above purification method, no ethyl ester was detected in the crude apixaban. Therefore, the ethyl ester was added to the crude apixaban having the purity shown in Table 2 to prepare a crude apixaban containing three impurities, methyl ester, ethyl ester, and carboxylic acid, with the purity shown in Table 6 below, and the crude apixaban was used in the following investigation.
試験例４：アピキサバンの再結晶による精製
上記の表６に示す純度を有するアピキサバン粗製物を用い、アセトニトリル／水（５：２）の混合溶媒、炭酸カリウム（０．０５当量）を加えて加熱攪拌した。溶解を確認した後、活性炭を加えて１０分間加熱攪拌し、セライトろ過により活性炭を除いた。得られたろ液を再度加熱し、高温度で水を加えた。水を加え終わった後に、２５℃まで冷却し、ろ過した。ろ過物を水及びエタノールで洗浄した後、４０℃で減圧乾燥し、アピキサバンを白色結晶として得た。
Test Example 4: Purification of Apixaban by Recrystallization Apixaban crude having the purity shown in Table 6 above was used, and a mixed solvent of acetonitrile/water (5:2) and potassium carbonate (0.05 equivalents) were added and heated and stirred. After dissolution was confirmed, activated carbon was added and heated and stirred for 10 minutes, and the activated carbon was removed by celite filtration. The obtained filtrate was heated again, and water was added at a high temperature. After the addition of water was completed, it was cooled to 25°C and filtered. The filtrate was washed with water and ethanol, and then dried under reduced pressure at 40°C to obtain apixaban as white crystals.
得られたアピキサバンの純度等は下記表７に示す通りであった。 The purity of the obtained apixaban was as shown in Table 7 below.
表中の結果から判明するように、本発明の精製方法により収率よく、高純度でアピキサバンが精製されており、本発明の特異性がよく理解されるものであった。 As can be seen from the results in the table, apixaban was purified with high yield and high purity by the purification method of the present invention, and the specificity of the present invention was clearly understood.
なお、本発明方法の特異性をより理解するために、参考として、特許文献１に記載される溶媒としてメタノール／水の混合溶媒を用い、塩基として炭酸ナトリウムを添加した再結晶を、表２に記載する純度を有するアピキサバンを用いて検討した。
その検討内容を試験例５として以下に記載し、結果を表８として示した。
In order to better understand the specificity of the method of the present invention, for reference, recrystallization using a mixed solvent of methanol/water as the solvent and adding sodium carbonate as the base as described in Patent Document 1 was investigated using apixaban having the purity shown in Table 2.
The details of the study are described below as Test Example 5, and the results are shown in Table 8.
試験例５：アピキサバンの精製（特許文献１を参考）
メタノール（１５０ｍＬ）に炭酸ナトリウム（０．８ｇ）を添加し、攪拌した。５０℃に加熱し、ｐＨ７．５－８であることを確認した。アピキサバン粗製物（３ｇ）を加えて、さらに加熱し、５５℃－６０℃まで昇温し、活性炭（０．０６ｇ）を加え、３０分攪拌した後、熱時ろ過により活性炭を除いた。得られたろ液に水（１５０ｍＬ）を添加し、３時間攪拌して晶析させた。結晶をろ過した。ろ過物を４０℃で減圧乾燥し、アピキサバンを白色結晶性の粉末として１．４３ｇ得た。収率は４７．７％であった。類縁物質個々最大はカルボン酸体で０．０５９％（メチルエステル体：０．０２４％）、純度は９９．８０７％であった。
Test Example 5: Purification of Apixaban (see Patent Document 1)
Sodium carbonate (0.8 g) was added to methanol (150 mL) and stirred. The mixture was heated to 50°C and confirmed to have a pH of 7.5-8. Apixaban crude product (3 g) was added and further heated to 55°C-60°C, activated carbon (0.06 g) was added, stirred for 30 minutes, and then the activated carbon was removed by hot filtration. Water (150 mL) was added to the obtained filtrate and stirred for 3 hours to cause crystallization. The crystals were filtered. The filtrate was dried under reduced pressure at 40°C to obtain 1.43 g of apixaban as a white crystalline powder. The yield was 47.7%. The maximum content of each related substance was 0.059% for the carboxylic acid form (methyl ester form: 0.024%), and the purity was 99.807%.
上記から判明するように、再結晶溶媒として特許文献１に記載のメタノール／水混合溶媒を使用し、塩基として炭酸ナトリウムを添加した場合であっても、再結晶溶媒の使用量が多量（１００倍量）なものであり、また、その再結晶収率も４７．７％と低いものであった。
その点から、本発明のアピキサバンの精製方法は、精製効率、収率および使用溶媒量の面で、極めて特異的なものであることが理解される。
As is clear from the above, even when the methanol/water mixed solvent described in Patent Document 1 was used as the recrystallization solvent and sodium carbonate was added as a base, the amount of the recrystallization solvent used was large (100 times the amount), and the recrystallization yield was low at 47.7%.
From this point of view, it can be understood that the method for purifying apixaban of the present invention is extremely unique in terms of purification efficiency, yield, and amount of solvent used.
なお、上記の各試験例における反応率分析条件は、以下のとおりである。
＜反応率分析条件＞
高速液体クロマトグラフ：Ｓｈｉｍａｚｕ ＬＣ-２０１０ＨＴ
検出器：紫外吸光光度計（測定波長：２８０ｎｍ）
カラム： ＩｎｅｒｔＳｕｓｔａｉｎ ＡＱ－Ｃ１８ ２５０×４．６ｍｍ ５．０μｍ
カラム温度：３０℃
移動相Ａ：緩衝液８００ｍＬとアセトニトリル２００ｍＬの混液
移動相Ｂ：緩衝液２００ｍＬとアセトニトリル８００ｍＬの混液
緩衝液：リン酸二水素カリウム１．３６ｇを水１０００ｍＬに溶解し、水酸化カリウム試液を加えてｐＨ６．０に調整した溶液
グラジエントテーブル：
The reaction rate analysis conditions in each of the above test examples are as follows.
<Conditions for reaction rate analysis>
High-performance liquid chromatograph: Shimazu LC-2010HT
Detector: ultraviolet spectrophotometer (measurement wavelength: 280 nm)
Column: InertSustain AQ-C18 250 x 4.6 mm 5.0 μm
Column temperature: 30°C
Mobile phase A: A mixture of 800 mL of buffer solution and 200 mL of acetonitrile. Mobile phase B: A mixture of 200 mL of buffer solution and 800 mL of acetonitrile. Buffer solution: A solution prepared by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 mL of water and adjusting the pH to 6.0 by adding potassium hydroxide TS. Gradient table:
流量：１．０ｍＬ／分
面積測定範囲：６０分
試料注入量：１０μＬ
サンプル希釈液：アセトニトリルと水が７：３の混液
サンプル濃度：０．５ｍｇのアピキサバンをサンプル希釈液１ｍＬに溶解
Flow rate: 1.0 mL/min Area measurement range: 60 min Sample injection volume: 10 μL
Sample diluent: A 7:3 mixture of acetonitrile and water Sample concentration: 0.5 mg of apixaban dissolved in 1 mL of sample diluent
＜上記した各試験例から本発明の特異性の理解＞
以上の各試験例から判明するように、本発明は、アピキサバンの再結晶溶媒としてアセトニトリル及び水の混合溶媒を使用し、塩基を加えて再結晶することで、収率よくアピキサバンを高純度に精製し得るものである。
前記したように、アピキサバンは難溶性の原薬であり、再結晶による精製では使用する溶媒量が多くなる。先行文献である特許文献１に記載の精製方法では、メチルエステル体およびカルボン酸体の除去率が低い。一方、本発明の精製方法（表７）は、特許文献１に記載に準じた精製方法（表８）と比較して、メチルエステル体およびカルボン酸体をいずれも約１／４に低減できる点で極めて特異的なものである。
<Understanding the specificity of the present invention from the above test examples>
As is evident from the above test examples, the present invention makes it possible to purify apixaban to a high purity with a high yield by using a mixed solvent of acetonitrile and water as a recrystallization solvent for apixaban and adding a base to perform recrystallization.
As described above, apixaban is a poorly soluble drug substance, and purification by recrystallization requires a large amount of solvent. The purification method described in the prior art, Patent Document 1, has a low removal rate of methyl ester and carboxylic acid. On the other hand, the purification method of the present invention (Table 7) is extremely unique in that it can reduce both methyl ester and carboxylic acid to about 1/4 compared to the purification method according to Patent Document 1 (Table 8).
さらに、本発明の精製方法はエチルエステル体に対する精製効果も高いものである。特許文献１に記載の精製方法では、５０倍量のメタノールに炭酸ナトリウムとアピキサバンを加えて溶解し、５０倍量の水を加えてアピキサバンを析出させており、使用溶媒量（合計１００倍量）が多く、収率も低い（４７．７％）ものである。
これに対して本発明の精製方法は、アセトニトリル／水の含水系でアピキサバンを溶解することで、２０倍量以下に溶媒量を抑制することが可能となり、有機溶媒単独よりも含水系とすることにより、アピキサバンが溶解し易く、再結晶収率も９０％以上と高いものである。
Furthermore, the purification method of the present invention is highly effective for purifying the ethyl ester. In the purification method described in Patent Document 1, sodium carbonate and apixaban are added to 50 times the amount of methanol to dissolve apixaban, and 50 times the amount of water is added to precipitate apixaban, which requires a large amount of solvent (100 times in total) and a low yield (47.7%).
In contrast, the purification method of the present invention dissolves apixaban in an aqueous system of acetonitrile/water, making it possible to reduce the amount of solvent to 20 times or less. By using an aqueous system rather than an organic solvent alone, apixaban is more easily dissolved, and the recrystallization yield is high, at 90% or more.
以上のとおり、本発明が提供する精製方法は、高品質かつ高収率でアピキサバンを精製し得ることが可能であり、生産性が高く工業的である。
また、本発明の精製方法で得られたアピキサバンは、さらに含水エタノールなどで再結晶することで医薬品として用いるには申し分のない高品質のアピキサバンを得ることができる点で、その産業上の利用性は多大なものである。
As described above, the purification method provided by the present invention is capable of purifying apixaban with high quality and in high yield, and is highly productive and industrially suitable.
Furthermore, apixaban obtained by the purification method of the present invention can be further recrystallized from aqueous ethanol or the like to obtain high-quality apixaban that is satisfactory for use as a pharmaceutical, and therefore the method has great industrial applicability.
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| CN106279149A (en) | 2015-06-02 | 2017-01-04 | 天津药物研究院有限公司 | A kind of method preparing high-purity Eliquis |
| CN108864090A (en) | 2018-08-03 | 2018-11-23 | 扬子江药业集团上海海尼药业有限公司 | A kind of preparation method of Eliquis N-1 crystal |
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| CN106188036A (en) | 2015-05-04 | 2016-12-07 | 中美华世通生物医药科技（武汉）有限公司 | The method of purification compound |
| CN106279149A (en) | 2015-06-02 | 2017-01-04 | 天津药物研究院有限公司 | A kind of method preparing high-purity Eliquis |
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